An optically active alcohol is useful as a chiral building block for synthesizing various optically active compounds. In general, an optically active alcohol is produced by optical resolution of a racemate, or an asymmetrical synthesis using a biological catalyst, asymmetric organocatalyst or asymmetric organometallic catalyst. The synthesis of an optically active alcohol by these asymmetric syntheses is considered to be an essential technique for production of optically active alcohol in a large scale.
Among the means for obtaining a optically active alcohol at a high efficiency, a method of asymmetric hydrogenation of a carbonyl compound in the presence of a ruthenium metal complex bearing a optically active diphosphine compound such as 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP), a optically active diamine compound in a ethylenediamine form, and a base such as a hydroxide of an alkaline metal or alkaline earth metal (Patent Literature 1), as well as a method of asymmetric hydrogenation of a carbonyl compound in the presence of an optically active diphosphine compound such as BINAP, a ruthenium metal complex bearing an ethylenediamine-type optically active diamine compound as a ligand, and a base such as a hydroxide of an alkaline metal or alkaline earth metal are disclosed (Patent Literature 2). However, in order to improve optical purity of the product of these method, i.e., the optically active alcohol, both diphosphine and diamine ligands have to be made optically active. Most of such optically active compounds used as ligands are expensive for their long synthetic pathways. Consequently, the complex is also expensive, producing a problem in its industrial use.
On the other hand, ruthenium complexes that have an achiral amine and an optically active diphosphine as ligands has also been known.
A ruthenium complex that has an optically active diphosphine and 2-picolylamine (PICA) as ligands can be synthesized at low cost because PICA is not an optically active compound. This complex is known to act as a catalyst for asymmetric transfar hydrogenation using 2-propanol as hydrogen source, reducing a ketone at a high efficiency (Patent Literature 3). In this literature, acetophenone is reacted under pressurized hydrogen condition using the ruthenium complex bearing an optically active 2,4-bis(diphenylphosphino)pentane (SKEWPHOS) and PICA as ligands, showing the results of 96% of conversion rate and 86% ee optical purity in only 2 hours under the condition of substrate concentration diluted at 0.1 mol/L, although a significant decrease in the optical purity is observed as compared to the same condition without pressurization of hydrogen (conversion rate 91%, optical purity 91% ee). In addition, when the substrate concentration was increased to 1.0 mol/L under pressurized hydrogen, 100% of conversion rate was reached after 17 hours, although the optical purity was markedly decreased to 39%, indicating that the addition of hydrogen did not effectively function. Moreover, said literature does not mention at all about that the optical purity of the generated alcohol would be improved by introducing a substituent onto PICA.
As an example of the use of a ruthenium complex bearing an optically active diphosphine and 2-picolylamine (PICA) as ligands for hydrogenation, the hydrogenation of tert-alkylketone using an ruthenium complex bearing an optically active diphosphine compound such as BINAP and 2-picolylamine has been reported (Patent Literature 4). However, the only diphosphine ligand exemplified in this literature is the diphosphine having an asymmetric structure to the axis such as BINAP. Said literature does not describe any reaction using as a catalyst a complex of diphosphine ligand having SKEWPHOS skeleton combined with 2-picolylamine, nor it refers to improving the optical purity of the generated alcohol by introducing a substituent onto PICA.
As an example of using a complex of diphosphine having SKEWPHOS skeleton with 2-picolylamine, the hydrogenation of 3-quinuclidinone (Patent Literature 5) and the hydrogenation of a heterocycle having a benzoyl group (Patent Literature 6) have been reported. However, the ketone substrates described in these literatures are only 3-quinuclidinone, 3-quinuclidinone having a substituent or a heterocycle having a benzoyl group, and there is no reference to reactions of simple ketones such as acetophenone. Furthermore, they do not refer to or suggest the likelihood of improving the optical purity of the generated alcohol compound by adding a substituent onto PICA.
As mentioned above, there has been no reports on an example wherein a ruthenium complex bearing a diphosphine having SKEWPHOS skeleton and a PICA ligand having more than one substituents on the pyridine ring or a ruthenium complex bearing as a ligand a heterocycle having more than one nitrogen atoms such as pyradine and pyrimidine effectively acts in the asymmetric hydrogenation of a carbonyl compound. Moreover, it has not been known the optical purity of the generated optically active alcohol can be improved as compared to using an unsubstituted PICA.